Composition and method for in vivo assay of opioid receptors

Abstract

Compositions and methods are provided to determine occupancy level of opioid receptors in a subject. The disclosed methods may be performed non-invasively in the inner ear of the subject, and may be performed at a point-of-care location to provide guidance to a practitioner on tapering on pharmacotherapy or on a patient's risk of relapse for substance abuse.

We claim: 
     
         1 . A compound of formula (I) or a salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         2 . A composition comprising the compound of  claim 1  and a carrier. 
     
     
         3 . A method for determining occupancy level of an opioid receptor in a subject, comprising:
 (a) contacting at least one probe with the subject, wherein the probe binds specifically to the opioid receptor (OR);   (b) measuring intensity of fluorescent signal emitted by the probe from inner ear of the subject; and   (c) determining the occupancy level of the opioid receptor in the subject based on the fluorescence intensity.   
     
     
         4 . The method of  claim 3 , wherein the probe comprises a compound having the formula (I) or a salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 3 , wherein step (b) is performed non-invasively. 
     
     
         6 . The method of  claim 3 , wherein fluorescence intensity in spiral ganglion is measured in step (b). 
     
     
         7 . The method of  claim 3 , wherein the fluorescence intensity is measured by using an oto-spectroscope. 
     
     
         8 . The method of  claim 3 , wherein the opioid receptor is mu opioid receptor (MOR). 
     
     
         9 . The method of  claim 3 , wherein the occupancy level of the opioid receptor in the subject is calculated quantitatively. 
     
     
         10 . The method of  claim 9 , wherein higher fluorescence intensity indicates lower occupancy level of the opioid receptor. 
     
     
         11 . The method of  claim 3 , further comprising administering an effective amount of an opioid antagonist or a partial opioid agonist to the subject based on the occupancy level of the opioid receptor in the subject. 
     
     
         12 . The method of  claim 11 , wherein the amount of the opioid antagonist or the partial opioid agonist administered is determined based on the occupancy level of the opioid receptor in the subject. 
     
     
         13 . The method of  claim 3 , wherein the probe is administered into the body of the subject in step (a). 
     
     
         14 . The method of  claim 3 , wherein the probe is administered by a means selected from the group consisting of nasal spray, intravenous (IV) injection, oral administration and skin patch. 
     
     
         15 . The method of  claim 3 , wherein the subject has been treated with a pain medication prescribed by a physician prior to step (a). 
     
     
         16 . The method of  claim 3 , wherein the method is used for preventing/treating opioid use disorder (OUD) or for monitoring response of a subject to treatment using an opioid antagonist. 
     
     
         17 . The method of  claim 3 , wherein the method is used for determining the dose of pharmacotherapy in the treatment of substance use disorder. 
     
     
         18 . The method of  claim 17 , wherein the substance use disorder is opioid use disorder. 
     
     
         19 . The method of  claim 17 , wherein the method is used to taper down the dosage of pharmacotherapy. 
     
     
         20 . The method of  claim 17 , wherein the subject is a pregnant woman with a substance use disorder and the method is used to reduce the risk of relapse in the subject. 
     
     
         21 . The method of  claim 3 , wherein excitation wavelength used in step (b) ranges between 635 nm and 760 nm 
     
     
         22 . The method of  claim 3 , further comprising a step of measuring rate of internalization of the probe. 
     
     
         23 . The method of  claim 22 , wherein two or more probes are used simultaneously. 
     
     
         24 . The method of  claim 22 , wherein the occupancy level of the opioid receptor and the rate of internalization of the probe are used to evaluate risk of developing an opioid use disorder in the subject. 
     
     
         25 . The method of  claim 3 , wherein the method is performed at point-of-care. 
     
     
         26 . The method of  claim 11 , wherein an opioid antagonist is administered, and the opioid antagonist is selected from the group consisting of alvimopan, norbinaltorphimine, nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically acceptable salts or prodrugs thereof. 
     
     
         27 . A kit for detecting an opioid receptor in a subject, comprising
 (c) a predetermined amount of compound of formula (I); and   
       
         
           
           
               
               
           
         
         (d) instruction for using the kit.